This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The aim of this project is to develop a new and general approach to the design and synthesis of easily programmable, disease-specific chemotherapeutic agents and probes that make direct use of genetic information to trigger the death of a diseased cell. The idea is to make use of a disease-specific mRNA or DNA sequence to direct the association of a pro-drug and an activator capable of converting the pro-drug to an active drug. In this approach the nucleic acid is used not as a target, but as a trigger, and thus does not depend on the biological activity of the disease-specific nucleic acid sequence, only on its uniqueness and accessibility. We are investigating the feasibility of one formulation of this new concept to chemotherapy in which the pro-drug component consists of a drug attached to a segment of PNA that is complementary to one section of a disease specific mRNA, and the activating component consists of a catalyst attached to a segment of PNA that i s c omplementary to the adjoining section of the mRNA. Only in a diseased cell can the disease specific mRNA cause the two components to associate which then results in the conversion of the pro-drug to a cytotoxic drug and death of the cell.